Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling (original) (raw)
Brief Definitive Report| February 07 2005
1Department of Cell Regulation, Medical Research Institute
2School of Biomedical Science, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
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1Department of Cell Regulation, Medical Research Institute
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3Department of Immune Regulation, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
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4Division of Infectious Genetics, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
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1Department of Cell Regulation, Medical Research Institute
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5Department of Oncology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
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6Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
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6Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
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5Department of Oncology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
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3Department of Immune Regulation, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
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4Division of Infectious Genetics, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
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1Department of Cell Regulation, Medical Research Institute
2School of Biomedical Science, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
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Hisaaki Shinohara
1Department of Cell Regulation, Medical Research Institute
2School of Biomedical Science, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
Akane Inoue
1Department of Cell Regulation, Medical Research Institute
Noriko Toyama-Sorimachi
3Department of Immune Regulation, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
Yoshinori Nagai
4Division of Infectious Genetics, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
Tomoharu Yasuda
1Department of Cell Regulation, Medical Research Institute
Hiromi Suzuki
5Department of Oncology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
Reiko Horai
6Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
Yoichiro Iwakura
6Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
Tadashi Yamamoto
5Department of Oncology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
Hajime Karasuyama
3Department of Immune Regulation, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
Kensuke Miyake
4Division of Infectious Genetics, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
Yuji Yamanashi
1Department of Cell Regulation, Medical Research Institute
2School of Biomedical Science, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
H. Shinohara's present address is Laboratory for Lymphocyte Differentiation, RIKEN Research Center for Allergy and Immunology, Kanagawa 230-0045, Japan.
Received: September 03 2004
Accepted: November 22 2004
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2005
J Exp Med (2005) 201 (3): 333–339.
Citation
Hisaaki Shinohara, Akane Inoue, Noriko Toyama-Sorimachi, Yoshinori Nagai, Tomoharu Yasuda, Hiromi Suzuki, Reiko Horai, Yoichiro Iwakura, Tadashi Yamamoto, Hajime Karasuyama, Kensuke Miyake, Yuji Yamanashi; Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling . _J Exp Med 7 February 2005; 201 (3): 333–339. doi: https://doi.org/10.1084/jem.20041817
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Endotoxin, a bacterial lipopolysaccharide (LPS), causes fatal septic shock via Toll-like receptor (TLR)4 on effector cells of innate immunity like macrophages, where it activates nuclear factor κB (NF-κB) and mitogen-activated protein (MAP) kinases to induce proinflammatory cytokines such as tumor necrosis factor (TNF)-α. Dok-1 and Dok-2 are adaptor proteins that negatively regulate Ras–Erk signaling downstream of protein tyrosine kinases (PTKs). Here, we demonstrate that LPS rapidly induced the tyrosine phosphorylation and adaptor function of these proteins. The stimulation with LPS of macrophages from mice lacking Dok-1 or Dok-2 induced elevated Erk activation, but not the other MAP kinases or NF-κB, resulting in hyperproduction of TNF-α and nitric oxide. Furthermore, the mutant mice showed hyperproduction of TNF-α and hypersensitivity to LPS. However, macrophages from these mutant mice reacted normally to other pathogenic molecules, CpG oligodeoxynucleotides, poly(I:C) ribonucleotides, or Pam3CSK4 lipopeptide, which activated cognate TLRs but induced no tyrosine phosphorylation of Dok-1 or Dok-2. Forced expression of either adaptor, but not a mutant having a Tyr/Phe substitution, in macrophages inhibited LPS-induced Erk activation and TNF-α production. Thus, Dok-1 and Dok-2 are essential negative regulators downstream of TLR4, implying a novel PTK-dependent pathway in innate immunity.
The Rockefeller University Press
2005
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